Project Summary: Copper enzymes that react with dioxygen are essential to our lives especially with respect to transforming biological molecules from one form to another. Yet, in areas of high metabolic activity such as the brain, mismanagement of copper resources is thought to lead to adventitiously bonded copper that reacts with dioxygen to form reactive dioxygen species (ROS) that lead to uncontrolled oxidative degradation of important biological molecules, ultimately leading to debilitating neurological diseases. Defining the ligation environment and the mechanism by which adventitiously bonded copper is able to create ROS is our overarching objective. As copper is the most labile of all redox active metals in biology, defining the coordination that leads to such ROS is challenging. Mechanisms of the reaction of copper with dioxygen in highly controlled coordination environments, such as proteins or in small copper complexes, provide a logical starting point to define what is chemically possible or if not what is chemically probable under less-defined, mismanaged conditions. We postulate that a mechanistic understanding of dioxygen activation and oxidative reactivity will inform on how best to attenuate ROS production at mismanaged copper sites. More specifically, binuclear copper sites that activate O2 and oxidize difficult substrates will be investigated in depth. We use a synthetic approach in our research whereby structurally-related low molecular weight complexes having faithful structural relationships to biological sites are examine for their oxidative reactive at a small molecule level of detail to reveal intrinsic structural, electronic, and properties. As our work lacks the superstructure of the biological systems, we use extremely low solution temperature to perform the investigation. The operating premise is that such complexes will provide important mechanistic insights to the oxidative (Cu(I) + O2) and reductive (Cu-O2 + substrate) half- reactions of biological systems if appropriate attention is directed to creating appropriate copper ligation environments.